The present invention relates to the use of riluzole or one of its pharmaceutically acceptable salts for the prevention and treatment of adrenoleukodystrophy.
Riluzole (2-amino-6-trifluoromethoxy-benzothiazole) is marketed for the treatment of amyotrophic lateral sclerosis (RILUTEK(copyright)). This compound is also useful as an anticonvulsant, an anxiolytic, and a hypnotic (EP 50551), in the treatment of schizophrenia (EP 305276), in the treatment of sleep disorders and of depression (EP 305277), in the treatment of cerebrovascular disorders and as an anaesthetic (EP 282971), in the treatment of spinal, cranial and craniospinal traumas (WO 94/13288), as a radio restorative (WO 94/15600), in the treatment of Parkinson""s disease (WO 94/15601), in the treatment of neuro-AIDS (WO 94/20103), and in the treatment of mitochondrial diseases (WO 95/19170).
X-linked adrenoleukodystrophy (ADL) is the most frequent of the genetic diseases of myelin, which is characterized by progressive demyelination of the central nervous system, an adrenal insufficiency and a moderate accumulation (3 to 5 times) of very long chain fatty acids (VLCFA) in most tissues, including the brain and the spinal cord. This accumulation of VLCFA results from a deficiency in their xcex2-oxidation in the peroxisome.
The mechanisms which lead in ALD to demyelination and loss of oligodendrocytes are still not well understood. One of the possibilities is that the accumulation of VLCFAs leads to a destabilization of the myelinic membranes or to a dysfunctioning of the receptors situated at the surface of the oligodendrocytes, making the receptors more sensitive to signals for programmed cell death (apoptosis). The death of the oligodendrocytes could also result from the production of cytokines (in particular TNF-xcex1 by the activated macrophages, which are present in the cerebral inflammatory lesions in ALD.
In a study of the fragmentation of the DNA, by the TUNEL method and by the expression of caspase-3, 50% of the oligodendrocytes of ALD patients, brains exhibit signs of cell death by apoptosis. Further, the intensity of the apoptotic phenomena is correlated with the intensity of the demyelination.
Death of the oligodendrocytes by apoptosis was recently demonstrated in several other murine models of genetic disease of myelin: in the twitcher mouse (model of Krabbe""s disease), and in various models such as jimpy mouse, msd mouse, and md rat (models deficient in proteolipid protein, PLP).
It has now been found that at least one active ingredient chosen from riluzole and its pharmaceutically acceptable salts reduces oligodendrocyte death from apoptosis induced by kainite. Thus, in one embodiment, the invention provides a method of treating adrenoleukodystrophy comprising administration of at least one active ingredient chosen from riluzole and its pharmaceutically acceptable salts.
The invention also provides a method of preventing adrenoleukodystrophy comprising administration of at least one active ingredient chosen from riluzole and its pharmaceutically acceptable salts.
In another embodiment, the invention relates to a method of preparing a medicament useful for the treatment of adrenoleukodystrophy comprising adding at least one active ingredient chosen from riluzole and its pharmaceutically acceptable salts, to the medicament.
The invention also relates to a method of preparing a medicament useful for the prevention of adrenoleukodystrophy comprising adding at least one active ingredient chosen from riluzole and its pharmaceutically acceptable salts, to the medicament.
The invention further relates to a method of preparing a medicament useful in the treatment of adrenoleukodystrophy comprising mixing at least one active ingredient chosen from riluzole and its pharmaceutically acceptable salts, with at least one compatible and pharmaceutically acceptable diluent and/or adjuvant.
The invention further relates to a method of preparing a medicament useful in the prevention of adrenoleukodystrophy comprising mixing at least one active ingredient chosen from riluzole and its pharmaceutically acceptable salts, with at least one compatible and pharmaceutically acceptable diluent and/or adjuvant.
In another embodiment, the invention relates to the method of treating adrenoleukodystrophy in a patient, comprising administering an effective amount of at least one active ingredient chosen from riluzole and its pharmaceutically acceptable salts to the patient.
The invention also relates to the method of preventing adrenoleukodystrophy in a patient, comprising administering an effective amount of at least one active ingredient chosen from riluzole and its pharmaceutically acceptable salts to the patient.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed. Reference will now be made in detail to exemplary embodiments of the present invention.
Pharmaceutically acceptable salts of riluzole include, but are not limited to, addition salts with inorganic acids such as, for example, hydrochloride, sulfate, nitrate, or phosphate, or with organic acids such as acetate, propionate, succinate, oxalate, benzoate, fumarate, maleate, methane-sulfonate, isethionate, theophyllineacetate, salicylate, phenolphthalinate, or methylene-bis-xcex2-oxy-naphthoate, and substitution derivatives of these derivatives.
The medicaments of the invention may comprise, for example, at least one riluzole compound, chosen from riluzole in free form, and riluzole in the form of an addition salt with a pharmaceutically acceptable acid. The at least one riluzole compound may be in a pure state or in the form of a composition in which it is combined with any other pharmaceutically compatible product, which may be inert or physiologically active. The medicaments according to the invention may, for example, be used by at least one of the oral, parenteral and rectal routes.
Solid compositions for oral administration may be chosen from, for example, tablets, pills, powders, gelatin capsules, cachets, and granules. In one embodiment, these compositions comprise the active ingredient according to the invention mixed with at least one inert diluent such as, for example, starch, cellulose, sucrose, lactose, and silica, under an argon stream. These compositions may also comprise substances other than diluents, such as, for example at least one of a lubricant, such as magnesium stearate or talc, a coloring, a coating (sugar-coated tablets), and a glaze.
Liquid compositions for oral administration may be chosen from, for example, pharmaceutically acceptable solutions, suspensions, emulsions, syrups, and elixirs. The liquid composition may further comprise inert diluents such as water, ethanol, glycerol, vegetable oils, and paraffin oil. These compositions may also comprise substances other than diluents, chosen from, for example wetting, sweetening, thickening, flavoring, and stabilizing products.
Sterile compositions for parenteral administration may be chosen from, for example, aqueous solutions, nonaqueous solutions, suspensions, and emulsions. As a solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate), and other suitable organic solvents may be used. These compositions may also contain adjuvants, including, for example, wetting agents, isotonizing agents, emulsifying agents, dispersing agents, and stabilizing agents.
The sterilization may be carried out in several ways, including, but not limited to, aseptisizing filtration, incorporating sterilizing agents into the composition, irradiation and heating. Sterile compositions can also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in sterile water or in any other injectable sterile medium.
The compositions for rectal administration may be, for example, suppositories or rectal capsules which may comprise, in addition to the at least one active ingredient, at least one excipient such as cocoa butter, semisynthetic glycerides, or polyethylene glycols.
The dose(s) of the active ingredient depends on the desired effect, on the duration of the treatment, and on the route of administration used. In one embodiment, the dose ranges from 50 mg and 400 mg per day by the oral route for an adult, with unit doses ranging from 25 mg to 200 mg of active substance.
In general, the doctor will determine the appropriate dosage according to the age, weight and all the other factors specific to the subject to be treated.
The invention will be illustrated by, but is not intended to be limited to, the following example.